Fecal Microbiota Transplantation: Current Status in Treatment of GI and Liver Disease

Fecal microbiota transplantation was originally introduced as a method to repair intestinal microbiota following failure of multiple treatments of recurrent Clostridium difficile infection with antibiotics. However, it is hypothesized that intestinal dysbiosis may contribute to the pathogenesis of many diseases, especially those involving the gastrointestinal tract. Therefore, fecal microbiota transplantation is increasingly being explored as a potential treatment that aims to optimize microbiota composition and functionality. Here, we review the current state of fecal microbiota transplantation development and applications in conditions of greatest interest to a gastroenterologist. Fecal microbiota transplantation was originally introduced as a method to repair intestinal microbiota following failure of multiple treatments of recurrent Clostridium difficile infection with antibiotics. However, it is hypothesized that intestinal dysbiosis may contribute to the pathogenesis of many diseases, especially those involving the gastrointestinal tract. Therefore, fecal microbiota transplantation is increasingly being explored as a potential treatment that aims to optimize microbiota composition and functionality. Here, we review the current state of fecal microbiota transplantation development and applications in conditions of greatest interest to a gastroenterologist. In recent years, fecal microbiota transplantation (FMT) has grown from a last-ditch procedure that challenged the aesthetic boundaries of medical practice to a widely practiced therapeutic option that has earned endorsement of professional societies in the treatment of antibiotic-refractory Clostridium difficile infection (CDI).1Surawicz C.M. Brandt L.J. Binion D.G. et al.Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.Am J Gastroenterol. 2013; 108 (quiz 499): 478-498Crossref PubMed Scopus (1253) Google Scholar, 2McDonald L.C. Gerding D.N. Johnson S. et al.Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).Clin Infect Dis. 2018; 66: 987-994Crossref PubMed Scopus (511) Google Scholar The term FMT supplanted earlier names such as bacteriotherapy or human probiotic infusion after documentation that infusion of donor fecal material results in prompt and sustained engraftment of donor bacteria.3Bakken J.S. Borody T. Brandt L.J. et al.Treating Clostridium difficile infection with fecal microbiota transplantation.Clin Gastroenterol Hepatol. 2011; 9: 1044-1049Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 4Khoruts A. Dicksved J. Jansson J.K. et al.Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea.J Clin Gastroenterol. 2010; 44: 354-360Crossref PubMed Scopus (508) Google Scholar The word microbiota refers to live microbial communities, and in addition to bacteria, feces also contain viruses and members of the Archaea and Eukarya domains of life. The contribution of these nonbacterial constituents of fecal microbiota is generating increasing interest with the growing appreciation of their roles in different human disease states and molding the overall microbial community structure and function.5Mukherjee P.K. Sendid B. Hoarau G. et al.Mycobiota in gastrointestinal diseases.Nat Rev Gastroenterol Hepatol. 2015; 12: 77-87Crossref PubMed Scopus (119) Google Scholar, 6Mirzaei M.K. Maurice C.F. Menage a trois in the human gut: interactions between host, bacteria and phages.Nat Rev Microbiol. 2017; 15: 397-408Crossref PubMed Scopus (180) Google Scholar, 7Ramanan D. Bowcutt R. Lee S.C. et al.Helminth infection promotes colonization resistance via type 2 immunity.Science. 2016; 352: 608-612Crossref PubMed Scopus (259) Google Scholar, 8Ishaq S.L. Sundset M.A. Crouse J. et al.High-throughput DNA sequencing of the moose rumen from different geographical locations reveals a core ruminal methanogenic archaeal diversity and a differential ciliate protozoal diversity.Microb Genom. 2015; 1: e000034PubMed Google Scholar The human gut microbiota is composed largely of symbiotic microorganisms selected for mutualistic interactions with the human host by co-evolution.9Dethlefsen L. McFall-Ngai M. Relman D.A. An ecological and evolutionary perspective on human-microbe mutualism and disease.Nature. 2007; 449: 811-818Crossref PubMed Scopus (1128) Google Scholar Thus, gut microbiota is integral to the function of the digestive tract and overall human physiology. It is important to appreciate that the human gut microbiota is not a mere assemblage of microorganisms, but a highly organized integrated network of microorganisms that interact intensely with each other as well as the host. Therefore, it can be thought of as an organ within the human body.10Backhed F. Ley R.E. Sonnenburg J.L. et al.Host-bacterial mutualism in the human intestine.Science. 2005; 307: 1915-1920Crossref PubMed Scopus (3614) Google Scholar The myriad of host–microbe and microbe–microbe interactions ensures fairly consistent content of genes, which constitutes the core microbiome across human beings.11Turnbaugh P.J. Hamady M. Yatsunenko T. et al.A core gut microbiome in obese and lean twins.Nature. 2009; 457: 480-484Crossref PubMed Scopus (5565) Google Scholar The ability of FMT to restore microbiota decimated by repeated antibiotic treatments in patients with multiply recurrent C difficile infections (rCDI) to a donor-like structure suggested a transplant equivalence.4Khoruts A. Dicksved J. Jansson J.K. et al.Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea.J Clin Gastroenterol. 2010; 44: 354-360Crossref PubMed Scopus (508) Google Scholar However, the analogy may not apply well in the absence of intensive antibiotic conditioning, such as that experienced by rCDI patients, in which FMT currently is used only as a last-resort treatment after failure of multiple courses of antibiotics.12Borody T.J. Khoruts A. Fecal microbiota transplantation and emerging applications.Nat Rev Gastroenterol Hepatol. 2012; 9: 88-96Crossref Scopus (473) Google Scholar The remarkable success of FMT in the treatment of rCDI has generated a great deal of enthusiasm for its use in other diseases that may be driven, at least partially, by host–microbiota interactions. Some of the obvious applications in gastroenterology include inflammatory bowel diseases (IBDs), irritable bowel syndrome (IBS), and liver diseases. The potential for FMT, as well as the optimal protocol for its administration, may vary significantly, depending on the underlying condition being treated. It is likely that repair of acute injury to the microbiota by antibiotics is fundamentally more straightforward relative to treatment of chronic diseases. Chronic inflammatory states are associated with an altered microbiome composition, which may be a consequence of altered gastrointestinal motility, diet, gut barrier function, oxygen tension, and many other factors intrinsic to a particular disease process. Nevertheless, FMT does have the potential for a major impact on microbiota, which undoubtedly participates in disease pathogenesis and represents a reasonable therapeutic target. Here, we review the recent advances in FMT used in different gastrointestinal conditions and highlight some of the immediate challenges and unknowns facing FMT development. The sheer scale of the CDI epidemic and the growing challenge of rCDI syndrome forced rapid adaptation of FMT. In 2013, the US Food and Drug Administration acknowledged FMT as a reasonable alternative after failures of standard options, which at the time were limited to antibiotics. CDI became the foundational disease for maturation of FMT as a therapeutic approach over the past decade. Clinical demand encouraged rapid technological development of FMT to become acceptable to mainstream medical practice. Some of the key early steps included standardization of donor selection and cryopreservation of donor microbiota, which allowed rigorous infectious disease testing and ready availability of donor material.13Hamilton M.J. Weingarden A.R. Sadowsky M.J. et al.Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection.Am J Gastroenterol. 2012; 107: 761-767Crossref PubMed Scopus (513) Google Scholar Frozen/thawed donor microbiota could be delivered via enemas, nasogastric or nasoduodenal tubes, or endoscopically. Subsequently, encapsulated frozen donor microbiota administered orally also has been shown to be highly efficacious in the treatment of rCDI.14Youngster I. Russell G.H. Pindar C. et al.Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection.JAMA. 2014; 312: 1772-1778Crossref PubMed Scopus (495) Google Scholar, 15Kao D. Roach B. Silva M. et al.Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial.JAMA. 2017; 318: 1985-1993Crossref PubMed Scopus (327) Google Scholar Recently, encapsulated freeze-dried preparations were introduced, which allows further simplification of handling and administration because of their stability at a range of temperatures.16Staley C. Hamilton M.J. Vaughn B.P. et al.Successful resolution of recurrent Clostridium difficile infection using freeze-dried, encapsulated fecal microbiota; pragmatic cohort study.Am J Gastroenterol. 2017; 112: 940-947Crossref PubMed Scopus (121) Google Scholar Today, FMT for the treatment of rCDI can be as simple as a single oral administration of a few capsules without any preceding colon purgative. This can seem remarkable to patients after they have struggled with many cycles of the infection and undergone multiple unsuccessful treatments with antibiotics. Indeed, it is not uncommon for some patients to wonder why FMT still remains only a last-resort treatment.17Khoruts A. Is fecal microbiota transplantation a temporary patch for treatment of Clostridium difficile infection or a new frontier of therapeutics?.Expert Rev Gastroenterol Hepatol. 2018; 12: 435-438Crossref PubMed Scopus (7) Google Scholar Of course, nothing about FMT fits the established, typical paradigms for therapeutics development. Although the US Food and Drug Administration classified FMT as a drug and a biologic, it is hardly comparable with any other drug in composition or formulation.18Hoffmann D. Palumbo F. Ravel J. et al.Improving regulation of microbiota transplants.Science. 2017; 358: 1390-1391Crossref PubMed Scopus (38) Google Scholar Similarly, its development did not follow the typical path of discovery, preclinical testing, and a series of carefully constructed clinical trials of progressively increasing size to test safety and efficacy. In fact, the usual preclinical testing in animals would make little sense because deliberate eating of feces (coprophagy) is a normal behavior in most mammals. In addition, human microbiota does not engraft easily into animals even after conditioning with antibiotics, and it will not fully interact with the animal host.19Staley C. Kaiser T. Beura L.K. et al.Stable engraftment of human microbiota into mice with a single oral gavage following antibiotic conditioning.Microbiome. 2017; 5: 87Crossref PubMed Scopus (93) Google Scholar, 20Chung H. Pamp S.J. Hill J.A. et al.Gut immune maturation depends on colonization with a host-specific microbiota.Cell. 2012; 149: 1578-1593Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar The latter observation is likely a consequence of co-evolution of indigenous gut microbiota with its host species, which selects for mutualist interactions; this contrasts with pathogen evolution, which commonly selects for microbe promiscuity with respect to different host species.21Ochman H. Worobey M. Kuo C.H. et al.Evolutionary relationships of wild hominids recapitulated by gut microbial communities.PLoS Biol. 2010; 8: e1000546Crossref PubMed Scopus (370) Google Scholar, 22Morens D.M. Folkers G.K. Fauci A.S. The challenge of emerging and re-emerging infectious diseases.Nature. 2004; 430: 242-249Crossref PubMed Scopus (1305) Google Scholar The initial uptake of FMT in clinical practice a decade ago built on a continuous trickle of anecdotal reports suggesting safety and remarkable efficacy since the 1950s.23Eiseman B. Silen W. Bascom G.S. et al.Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis.Surgery. 1958; 44: 854-859PubMed Google Scholar, 24Persky S.E. Brandt L.J. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope.Am J Gastroenterol. 2000; 95: 3283-3285PubMed Google Scholar, 25Aas J. Gessert C.E. Bakken J.S. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube.Clin Infect Dis. 2003; 36: 580-585Crossref PubMed Scopus (425) Google Scholar Current safety concerns about FMT continue to focus on the risk of infectious disease transmission. In 2011, the FMT Workgroup developed and published consensus recommendations on donor testing, which became the foundational document for multiple professional societies and the US Food and Drug Administration.3Bakken J.S. Borody T. Brandt L.J. et al.Treating Clostridium difficile infection with fecal microbiota transplantation.Clin Gastroenterol Hepatol. 2011; 9: 1044-1049Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar The donor testing requirements continue to expand, especially as laboratory methods for pathogen detection improve and increased rigor becomes feasible with the adoption of the universal stool bank model.26Cammarota G. Ianiro G. Tilg H. et al.European consensus conference on faecal microbiota transplantation in clinical practice.Gut. 2017; 66: 569-580Crossref PubMed Scopus (617) Google Scholar The scarcity of reports on infectious disease transmission with FMT despite its growing worldwide utilization suggests that the infectious risk is very small. This could be an indication of the effectiveness of the current screening and testing protocols. It is noteworthy that FMT thus far has proved to be safe even in highly immunosuppressed patients.27Kelly C.R. Ihunnah C. Fischer M. et al.Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients.Am J Gastroenterol. 2014; 109: 1065-1071Crossref PubMed Scopus (457) Google Scholar, 28Kakihana K. Fujioka Y. Suda W. et al.Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut.Blood. 2016; 128: 2083-2088Crossref PubMed Scopus (221) Google Scholar, 29DeFilipp Z. Peled J.U. Li S. et al.Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity.Blood Adv. 2018; 2: 745-753Crossref PubMed Scopus (123) Google Scholar Nevertheless, as in any young field, there are many challenges and areas of uncertainty, and stool donor selection protocols continue to evolve.30Woodworth M.H. Carpentieri C. Sitchenko K.L. et al.Challenges in fecal donor selection and screening for fecal microbiota transplantation: a review.Gut Microbes. 2017; 8: 225-237Crossref PubMed Scopus (62) Google Scholar Nucleic acid–based technologies largely have replaced culture-based methods for enteric pathogen testing and offer the potential of rapid detection of a broader range of established and suspected pathogens. However, the sensitivity of these diagnostics on formed stool of asymptomatic individuals is unknown and there is an increased false-positive discovery rate of low-prevalence infections. True virulence and strain diversity of some suspected pathogens are unknown. An illustrative case study is Blastocystis. Some groups recommend exclusion of donors found to harbor Blastocystis, regardless of subtype.26Cammarota G. Ianiro G. Tilg H. et al.European consensus conference on faecal microbiota transplantation in clinical practice.Gut. 2017; 66: 569-580Crossref PubMed Scopus (617) Google Scholar, 31Roberts T. Stark D. Harkness J. et al.Subtype distribution of Blastocystis isolates identified in a Sydney population and pathogenic potential of Blastocystis.Eur J Clin Microbiol Infect Dis. 2013; 32: 335-343Crossref PubMed Scopus (49) Google Scholar However, in some studies, colonization with Blastocystis has been associated with higher microbiome diversity (a possible marker of greater microbial community resilience), as well as lesser incidence of IBD and IBS.32Audebert C. Even G. Cian A. et al.Colonization with the enteric protozoa Blastocystis is associated with increased diversity of human gut bacterial microbiota.Sci Rep. 2016; 6: 25255Crossref PubMed Scopus (162) Google Scholar, 33Krogsgaard L.R. Engsbro A.L. Stensvold C.R. et al.The prevalence of intestinal parasites is not greater among individuals with irritable bowel syndrome: a population-based case-control study.Clin Gastroenterol Hepatol. 2015; 13: 507-513 e2Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 34Rossen N.G. Bart A. Verhaar N. et al.Low prevalence of Blastocystis sp. in active ulcerative colitis patients.Eur J Clin Microbiol Infect Dis. 2015; 34: 1039-1044Crossref PubMed Scopus (49) Google Scholar Clearly, our knowledge even of microorganisms that have been areas of interest for decades is far from complete and we can expect donor testing for infectious disease to remain a highly dynamic area in microbiota therapeutics development. Because gut microbiota potentially plays important roles in various aspects of host physiology, stool donor selection criteria generally go beyond infectious disease testing and consider potential long-term effects of FMT on energy metabolism, immune function, and even neurologic and psychiatric health.3Bakken J.S. Borody T. Brandt L.J. et al.Treating Clostridium difficile infection with fecal microbiota transplantation.Clin Gastroenterol Hepatol. 2011; 9: 1044-1049Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 13Hamilton M.J. Weingarden A.R. Sadowsky M.J. et al.Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection.Am J Gastroenterol. 2012; 107: 761-767Crossref PubMed Scopus (513) Google Scholar, 26Cammarota G. Ianiro G. Tilg H. et al.European consensus conference on faecal microbiota transplantation in clinical practice.Gut. 2017; 66: 569-580Crossref PubMed Scopus (617) Google Scholar, 30Woodworth M.H. Carpentieri C. Sitchenko K.L. et al.Challenges in fecal donor selection and screening for fecal microbiota transplantation: a review.Gut Microbes. 2017; 8: 225-237Crossref PubMed Scopus (62) Google Scholar The underlying concern is that the intestinal microbiota potentially could contribute to the pathogenesis of diseases such as metabolic syndrome, IBD, allergies, colon cancer, and many others. This potential for harm is based on the exact same hypotheses that justify exploration of FMT as a potential strategy to treat such diseases. For example, administration of stool from lean donors has shown some promise in improving insulin sensitivity of prediabetic patients.35Vrieze A. Van Nood E. Holleman F. et al.Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.Gastroenterology. 2012; 143: 913-916 e7Abstract Full Text Full Text PDF PubMed Scopus (1909) Google Scholar, 36Kootte R.S. Levin E. Salojarvi J. et al.Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition.Cell Metab. 2017; 26: 611-619 e6Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar Conversely, microbiota from obese, but not lean, human beings has led to greater weight gain in germ-free mice.37Ridaura V.K. Faith J.J. Rey F.E. et al.Gut microbiota from twins discordant for obesity modulate metabolism in mice.Science. 2013; 341: 1241214Crossref PubMed Scopus (2421) Google Scholar Thus far, clinical FMT experience in treatment of CDI patients has not generated clear evidence for the potential transfer of obesity,38Fischer M. Kao D. Kassam Z. et al.Stool donor body mass index does not affect recipient weight after a single fecal microbiota transplantation for Clostridium difficile infection.Clin Gastroenterol Hepatol. 2018; 16: 1351-1353Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar although 1 clinical anecdote did generate some publicity.39Alang N. Kelly C.R. Weight gain after fecal microbiota transplantation.Open Forum Infect Dis. 2015; 2: ofv004Crossref PubMed Scopus (292) Google Scholar Similarly, donor stool from an individual who 1 year later developed bloody diarrhea and was diagnosed with ileocolonic Crohn’s disease did not transfer Crohn’s disease to any of the 31 CDI recipients.40Fischer M. Bittar M. Papa E. et al.Can you cause inflammatory bowel disease with fecal transplantation? A 31-patient case-series of fecal transplantation using stool from a donor who later developed Crohn's disease.Gut Microbes. 2017; 8: 205-207Crossref PubMed Scopus (13) Google Scholar These inadvertently generated data, although somewhat reassuring, highlight the fact that most stool donors are healthy by virtue of being young and we currently do not have any reliable microbiome-specific metrics to define healthy microbiota. Of course, this remains a critical objective for the microbiome science, whether it is focused on the development of therapeutics or diagnostics. The compositional uncertainty of FMT products is potentially unsettling to providers, regulators, and patients. This is a legitimate concern and one of the driving forces for the development of defined therapeutic microbial consortia. However, it is far from obvious or certain that such products will necessarily be safer, even if equal in short-term efficacy when measured by a single end point such as cessation of CDI recurrence.17Khoruts A. Is fecal microbiota transplantation a temporary patch for treatment of Clostridium difficile infection or a new frontier of therapeutics?.Expert Rev Gastroenterol Hepatol. 2018; 12: 435-438Crossref PubMed Scopus (7) Google Scholar However, this issue is not clearly limited to FMT products because although we have fairly detailed and sophisticated knowledge about the make-up and mechanisms of antibiotic drugs, for decades we have ignored their profound off-target effects on indigenous microbiota. Now, it appears possible that widespread use of antibiotics may have contributed to the many epidemics of modern diseases, such as metabolic syndrome and autoimmunity.41Blaser M.J. The theory of disappearing microbiota and the epidemics of chronic diseases.Nat Rev Immunol. 2017; 17: 461-463Crossref PubMed Scopus (101) Google Scholar In addition, the neglect of antibiotic effects on indigenous microbiota is the major driver of antibiotic resistance, which is one of the greatest emergent threats in modern medicine. FMT has opened a new frontier in therapeutics development. It recognizes microbiota as a human organ that can be repaired. It provides a restorative approach that actually lowers the burden of antibiotic resistance genes in rCDI patients.42Millan B. Park H. Hotte N. et al.Fecal microbial transplants reduce antibiotic-resistant genes in patients with recurrent Clostridium difficile infection.Clin Infect Dis. 2016; 62: 1479-1486Crossref PubMed Scopus (127) Google Scholar Although current donor selection methodology cannot predict some potential off-target long-term effects of treatment, it does mitigate that risk with a rational approach that is likely superior to the game of chance each person engages in early in life, assembling their microbiota from their mother and the environment. Many immediate challenges remain in FMT development. Although encapsulated products for oral administration already have entered clinical practice, it is likely that considerable work still is required to optimize consistent distal gut delivery of viable microbiota. Simple and convenient FMT therapeutics may become front-line agents for the treatment and prevention of CDI, but clearly large clinical trials comparing FMT against current standard initial treatments have yet to be performed. It is noteworthy that a small fraction of rCDI patients repeatedly fail FMT. The mechanisms of failure remain unknown and require better understanding of how FMT works.43Khoruts A. Sadowsky M.J. Understanding the mechanisms of faecal microbiota transplantation.Nat Rev Gastroenterol Hepatol. 2016; 13: 508-516Crossref PubMed Scopus (271) Google Scholar Achieving such understanding requires systematic mechanistic studies to accompany clinical trials as well as everyday practice of FMT. The full appreciation of the various unintended effects of health care–induced dysfunction in gut microbiota is still only emerging. Three examples that are ripe for intensive investigations are as follows: (1) optimization of checkpoint immunotherapy; (2) normalization of gut microbiota in the setting of critical illness and sepsis; and (3) mitigating complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent reports have suggested that efficacy of checkpoint immunotherapy is dependent on the state of the gut microbiota.44Gopalakrishnan V. Spencer C.N. Nezi L. et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (2218) Google Scholar, 45Matson V. Fessler J. Bao R. et al.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018; 359: 104-108Crossref PubMed Scopus (1428) Google Scholar, 46Routy B. Le Chatelier E. Derosa L. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (2587) Google Scholar Tumor-bearing mice do not benefit as well from antibodies targeting programmed cell death protein 1 or cytotoxic T-lymphocyte–associated protein 4 if treated with broad-spectrum antibiotics. Similarly, the efficacy of immunotherapy, as measured by progression-free and overall survival, was decreased in patients who took antibiotics for common indications such as dental, urinary, and pulmonary infections.46Routy B. Le Chatelier E. Derosa L. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (2587) Google Scholar These effects of antibiotics are thought to be owing to disruption of microbiota-derived signals that promote antitumor immune responses, such as effector T-cell differentiation and activity. FMT may be a reasonable strategy to correct these antibiotic-induced defects. Liberal use of broad-spectrum antibiotics and a lack of microbiota-accessible enteral nutrient flow is a common situation in critically ill hospitalized patients. These interventions result in rapid and profound depletion of intestinal microbiota and emergence of low-diversity microbial communities enriched for pathobionts and multidrug-resistant health care–associated pathogens.47Krezalek M.A. DeFazio J. Zaborina O. et al.The shift of an intestinal “microbiome” to a “pathobiome” governs the course and outcome of sepsis following surgical injury.Shock. 2016; 45: 475-482Crossref PubMed Scopus (102) Google Scholar Loss of healthy microbiota and associated microbiota-derived tonic stimulation leads to reductions in epithelial tight junction integrity, regulatory T cells, secretory IgA, mucus, and antimicrobial peptides. Collectively, these mechanisms lead to gut barrier dysfunction, translocation of potential pathogens, and increased systemic inflammatory response. These changes increasingly are hypothesized to be the engine of multiple organ failure, which can develop in critical illness. Not surprisingly, some investigators are turning to FMT as a potential strategy to heal the microbiota.48McClave S.A. Patel J. Bhutiani N. Should fecal microbial transplantation be used in the ICU?.Curr Opin Crit Care. 2018; 24: 105-111Crossref PubMed Scopus (23) Google Scholar Thus far, the literature is limited to case reports.49Li Q. Wang C. Tang C. et al.Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report.Crit Care. 2015; 19: 37Crossref PubMed Scopus (75) Google Scholar, 50Wurm P. Spindelboeck W. Krause R. et al.Antibiotic-associated apoptotic enterocolitis in the absence of a defined pathogen: the role of intestinal microbiota depletion.Crit Care Med. 2017; 45: e600-e606Crossref PubMed Scopus (31) Google Scholar, 51Wei Y. Yang J. Wang J. et al.Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis.Crit Care. 2016; 20: 332Crossref PubMed Scopus (83) Google Scholar, 52Li Q. Wang C. Tang C. et al.Therapeutic modulation and reestablishment of the intestinal microbiota with fecal microbiota transplantation resolves sepsis and diarrhea in a patient.Am J Gastroenterol. 2014; 109: 1832-1834Crossref PubMed Scopus (42) Google Scholar These reports, however, share the accounts of rapid reduction in the systemic inflammatory response syndrome metrics, similar to observations in patients treated with FMT for severe complicated pseudomembranous colitis associated with CDI.23Eiseman B. Silen W. Bascom G.S. et al.Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis.Surgery. 1958; 44: 854-859PubMed Go